Retinal diseases are various depending upon their causes of the diseases and modes of the onset of the diseases. Examples of retinal diseases are retinal vascular disorders and inflammatory or degenerative lesions resulting from systemic diseases such as diabetes, hypertension, arteriosclerosis, anemia, leukemia, connective tissue diseases (e.g., systemic lupus erythematosus, scleroderma, etc.), diseases of congenital metabolism anomaly (e.g., Tay-Sachs diseases, Vogt-Spielmeyer diseases, etc.), and, retinal local diseases such as retinal vascular disorders (e.g., retinopathy of prematurity, retinal vein obstruction, retinal artery obstruction, retinal periphlebitis, etc.), retinal inflammations or degeneration derived from retinal detachment or trauma, retinal degenerative diseases accompanying an aging such as senile disciform macular degeneration, congenital retinal degenerative diseases and the like.
Representatives of these retinal diseases are further described below.
Among the retinal diseases resulting from systemic diseases, diabetic retinopathy is recognized as one of the diabetic microangiopathies which are severe complications of diabetes. In the initial stage, capillary microaneurysm and dot hemorrhage are observed. Thereafter, cotton wool patches resulting from microvascular obstruction, and retinal edema, hard exudates or the like resulting from vascular hyperpermeability are observed. Luxuriant changes accompanied by neovascularization appear as the symptoms. In the last stage, retinal detachment is caused by the traction of connective tissues grown in vitreous body. Further, iris rubeosis and neovascular glaucoma are caused, leading to blindness.
Retinae of patients with hypertension manifests hypertensive changes such as arteriolar narrowing or hemorrhage, exudative patches, retinal and optic disk edema and the like; sclerotic changes such as arteriolar sclerosis, arteriovenous crossing phenomena, arterial narrowing, unequal caliber and the like.
Retinal lesions of leukemia include remarkable enlargement of retinal veins, exudation into peri-venous tissue and hemorrhage of various size and shape around the posterior pole. In addition, modular exudate, cotton wool patches resulting from microvascular obstruction, and retinal edema are observed.
Systemic lupus erythematosus is one of the autoimmune diseases manifesting systemic lesions such as eruption, acute nephritis or the like. Retinae of patients with this disease manifest cotton wool patches and sporadic retinal hemorrhage around the posterior pole. In addition, optic disk edema and peripheral vascular inflammation are sometimes observed.
Congenital metabolism anomaly such as the Tay-Sachs disease, Vogt-Spielmeyer disease sometimes exhibits ophthalmopathies as well as systemic symptoms. Typical retinal symptoms are cherry red spots or pigmentary lesions and sometimes complicated by optic nerve atrophy.
Among retinal local diseases, the retinal vein obstruction can be classified into central retinal vein obstruction and branch retinal vein obstruction depending upon the site of the obstruction. The central retinal vein obstruction produces congestion and edema in the optic disk. Blood spots are often observed in the optic disk surface. The retina becomes edematous and manifests cotton wool patches soon. In the branch retinal vein obstruction, radial hemorrhage is seen in the region and retinal edema and cotton wool patches appear.
Also in the retinal artery obstruction, there are central retinal artery obstruction and branch retinal artery obstruction. Soon after artery obstruction occurs, the retina becomes slightly opaque. A few hours later, milk white and edematous retinal opacity is observed and becomes irreversible within 20 to 30 minutes after the obstruction. A few weeks later, the above opacity disappears and the internal layer of the retina is replaced with transparent glia tissues. The obstruction of retinal artery or vein sometimes develops based on hypertension or arteriosclerosis as systemic diseases.
Retinal periphlebitis is an inflammatory disease occurring in the peripheral branches of retinal vein. Findings such as the vein enlargement, bending, unequal caliber, vascular peripheral exudative patches, hemorrhage, neovascularization and the like are observed.
Retinopathy of prematurity is a disease caused when a baby born as a premature infant is housed in a closed incubator and exposed to a high concentration of oxygen. As a result, irreversible obstruction accompanied by vascular endothelial cellular proliferation occurs and later results in neovascularization into vitreous body and retinal detachment.
Retinal detachment is a disease wherein sensory retinae and retinal pigment epithelium are separated. There are rhegmatogenous retinal detachment resulting from retinal tear and secondary retinal detachment occurring in the course of other diseases or resulting from other diseases. These retinal detachments lead to retinal degeneration resulting in blindness unless they are treated by immediate operative therapy such as photocoagulation.
In the senile disciform macular degeneration, neovascularization occurs in the yellow spots from the choroid through Bruch's membrane into under the retinal pigment epithelium. The neogenetic blood vessels grow and also penetrate into subretinal space. The serous exudate from the blood vessels results in retinal pigment epithelium detachment and disciform detachment of the macula. Hemorrhage is repeated mainly in loci containing neogenetic blood vessels and leads to scarring of the foci.
Congenital pigmentary degeneration of the retina occurs in children. Night blindness is observed, and narrowing of visual field and failing of the eyesight gradually proceed. The fundus changes are characterized by pigmentary lesions, yellow atrophy of the optic disk, narrowing of retinal blood vessels, particularly retinal artery.
As methods for treating the various diseases described above, systemic causal therapies may be applied in the case of retinal diseases resulting from systemic diseases. Examples thereof are administration of hypotensive agents against hypertension, administration of hypoglycemic agents against diabetes and the like. However, only these therapies do not always relieve the retinal lesions. Further, in the case of autoimmune diseases and congenital metabolism anomaly, casual therapies are sometimes very difficult or impossible. Treatments for retinal local lesions are therefore required. In this case, pharmacotherapies with vasodilators, vessel wall stabilizers or thromboclastic agents are applied against retinal vascular lesions in diabetes, hypertension or the obstruction of retinal artery or vein. However, these pharmacotherapies are symptomatic and not definitive, and treatment of the diseases often depends upon operative therapies now.
As described above, there is no definitive agent for preventing and treating the above retinal diseases. Under these circumstances, the present inventors have intensively studied to obtain an agent for preventing or treating the above retinal diseases.
As described above, retinal diseases manifest various symptoms including inflammations such as retinal vascular disorders, vascularization, retinal edema, and primary or secondary retinal degeneration and the like. Each disease leads more or less to disorders of retinal functions. Accordingly, the present inventors have advanced investigations from the following two points of view. The first point of view is that the development and progress of the above retinal diseases may be based on or associated with ischemic or hypoxic states and peroxidation induced by the states. The second point of view is that, in view of the special characteristics of retinal functions that eyesight is exhibited by receiving light, excess light itself may be one of the risk factors of these retinal diseases.
With regard to the first point of view, the theory which has become powerful recently is that vascular lesions in diabetic retinopathy are reactions to hypoxic or ischemic states of tissues. Further, there is a report that the lipidperoxide level in the serum of patients was increased by peroxidation considered to be induced by ischemia (Kiyoshi Ishikawa, Masayuki Oshitari et al., Lipidperoxides and retinal ischemia in diabetic retinopathy (I), Folia Ophthalmologica Japonica 28:321-325 (1977)). Furthermore, retinal arteriovenous obstruction results in ischemia, and peroxidation is also considered to be associated with this case.
With regard to the second point of view, there is a report that the progress of retinal degeneration was retarded when congenital retinal dystrophic rats were reared in the dark (Dowling, J. E. and Sidman, R. L.: Inherited retinal dystrophy in the rat; J. Cell Biol. 14:73-109 (1962)). In the case of these rats, the retinal degeneration results from errors in the phagocytosis of retinal pigment epithelial cells renewing outer segments of retinal visual cells with visual ability. In the state wherein the metabolic equilibrium is lost, light itself is shown to promote the destruction of visual cells. There is a report that retinal degeneration was caused in normal animals by intensive exposure to light (Shahinfar, S., Edward, D. P. and Tso, M. O. M.: A pathologic study of photoreceptor cell death in retinal photic injury; Cuur. Eye Res. 10:47-59 (1991)). It can be said that excess light is one of the risk factors of retinal diseases.
By the way, the following reports are made recently. The reports are on the synthesis of ascorbic acid derivatives having a substituent at the 2-position and their antioxidative activity (see EP-A-0146121); on improving effects on circulatory systems such as antiarrhythmic activity, anticardiac infarction activity, anti-cerebral infarction activity, prophylactic effect against senile dementia based on its free-radical scavenging activity of the ascorbic acid derivatives (EP-A-0202589); on therapeutic effects against cataract of a part of the above ascorbic acid derivatives and their bioavailability and preparation (see JP-A 63-301818).
From the above two points of view, the present inventors have studied to obtain compounds which inhibit the peroxidation of retinae or retinal disorders caused by light. As a result, it has been found that the compounds described in the above EP-A-0146121 and EP-A-0202589 include compounds having surprisingly excellent both effects described above. Thus, the present invention has been completed.